1. Field of the Invention
The present invention provides a new method for the formation of functionalized aryl-alkyl bonds, particularly aryl-aralkyl bonds. In particular, the invention provides methods of synthesizing active dihydrofolate reductase (DHFR) inhibitors and new classes of DHFR inhibitors particularly where a substituted aryl group is linked to a diamino substituted heterocyclic moiety via a methylene group.
2. Background
Piritrexim (1), a lipophilic inhibitor of the key metabolic enzyme dihydrofolate reductase (DHFR) has been studied intensively as an anticancer drug, and more recently was identified as a potent inhibitor of the enzyme from Pneumocystis carinii (Pc) and Tozoplasma gondii (Tg), two opportunistic parasites known to be potentially life-threatening in patients with acquired immunodeficiency syndrome (AIDS). See, for example, Grivsky, E. M.; Lee, S.; Sigel, C. W.; Duch, D. S.; Nichol, C. A. J. Med Chem. 1980; 23, 327-329; Sigel, C. W.; Macklin, A. W.; Woolley, J. L., Jr.; Johnson N. W.; Collier, M. A.; Blum, M. R.; Clendeninn, N. J.; Everitt, J. M.; Grebe, G.; Mackars, A.; Foss, R. G.; Duch, D. S.; Bowers, S. W.; Nichol, C. A. NCI Monogr. 1987; 5, 111-120; Laszlo, J.; Brenckman, W. D., Jr.; Morgan, E.; Clendeninn, N. J.; Williams, T.; Currie, V.; Young, C. NCI Monogr. 1987; 5, 121-125; and Kovacs, J.; Allegra, C. A.; Swan, J. C.; Drake, J. C.; Parrillo, J. E.; Chabner, B. A.; Masur, H. Antimicrob. Agents Chemother. 1988; 32, 430-433. A notable structural feature of 1 is the short CH2 bridge between the two halves of the molecule. This bridge is also present in trimethoprim (2), another lipophilic DHFR inhibitor widely used to for anti-Pc and anti-Tg prophylaxis and therapy in AIDS patients, usually in combination with a sulfa drug to enhance efficacy. For an excellent historical account of the chemical and pharmaceutical development of the older lipophilic DHFR inhibitors pyrimethamine and trimethoprim, see: Roth, B.; Cheng, C. C. Progr. Med Chem. 1982; 19, 269-331; Fischl, M. A.; Dickinson, G. M.; La Voie, L. J. Am. Med. Assoc. 1988; 259, 1185-1189; and Medina, I.; Mills, J.; Leoung, G.; Hopewell, P. C.; Lee, B.; Modin, G.; Benowitz, N.; Wofsy, C. B. N. Engl. J Med 1990; 323, 776-782. Two other members of this class that have been used clinically against these infections are pyrimethamine (3), in which the two halves of the molecule are linked without a CH2 bridge, and trimetrexate (4), which contains a longer CH2NH bridge. In addition to the fact that it contains a longer bridge, 4 differs from 1 in being a quinazoline as opposed to a pyrido[2,3-d]pyrimidine. See for example, Bertino, J. R.; Sawicki, W. L.; Moroson, B. A.; Cashmore, A. R.; Elslager, E. F. Biochem. Pharmacol. 1979; 28, 1983-1987; Elslager, E. F.; Johnson, E. L.; Werbel, L. M. J. Med Chem. 1983; 26, 1753-1760; and Sattler, F. R.; Frame, P.; Davis, R.; Nichols, L.; Shelton, B.; Akil, B.; Baugman, R.; Hughlett, C.; Weiss, W.; Boylen, C. T.; van der Horst, C.; Black, J.; Masur, H.; Feinberg, J. J. Infect. Dis. 1994; 170, 165-172.

There has been reported examples of certain lipophilic DHFR inhibitors in which the fused 2,4-diaminopyrimidine ring system and the aryl side chain are separated by a short O or S bridge, as in 5 and 6. The only quinazoline antifolates reported to date, however, in which the bridge is CH2 are the 5,6,7,8-tetrahydro derivatives 7. See for example Elslager, E. F.; Clarke, J.; Johnson, J.; Werbel, L. M. Davoll, J. J. Heterocycl. Chem. 1972; 9, 759-773; Hynes, J. B.; Ashton, W. T.; Merriman, H. G., III, Walker, F. C., III. J. Med Chem. 1974; 17, 682-684; and Rosowsky A; Papoulis, A. T.; Forsch, R. A.; Queener, S. F. J. Med Chem. 1999; 42, 1007-1017.

It would be desirable to have new methods for synthesis of biologically active DHFR inhibitors.